Current Treatment Modalities, Available Therapeutics for Prostate Cancer See Growth

Prostate cancer is the secondmost-common cancer in American men and the second-leading cause of cancer death in the United States.^1,2 In 2022 alone, the American Cancer Society estimates 268,490 new cases of prostate cancer in the country and 34,500 deaths.2 As men live longer, their chances of having prostate cancer increase.^1,2

Although incidence of prostate cancer has nearly doubled over the past 20 years, early detection and improved treatment modalities have significantly decreased deaths associated with the disease.¹

Background
Located below the bladder, the prostate is a walnut-sized gland in males that stores seminal fluid, a liquid that nourishes sperm.^1,2 Almost all prostate cancers are adenocarcinomas that develop from these gland cells.² Although the exact cause of prostate cancer remains unknown, the growth of cancer cells is known to be stimulated by the male hormone testosterone.^1,2

Several factors may increase the risk of developing prostate cancer, including age (> 50 years); genetic predisposition/ family history, such as BRCA1 or BRCA2 genes or Lynch syndrome (hereditary nonpolyposis colorectal cancer); and a high-fat diet.^1,2 African American men are also twice as likely as non-Hispanic White men to receive prostate cancer diagnoses, whereas the disease occurs less frequently in Asian and Hispanic men.^1,2 Prostate cancer can often be detected early before a man experiences signs or symptoms; some prostate cancers grow so slowly that they may never cause issues.^1,2 Prostate-specific antigen (PSA) levels in a man’s blood and a digital rectal examination (DRE) are the current standards for initial screening.^2,3

Approximately 80% of prostate cancers are diagnosed at an early, more treatable stage, with the survival rate for these patients at almost 100%.^1,2 Abnormal findings in PSA or DRE may warrant biopsy to pathologically confirm a diagnosis of cancer.^2,3 If cancer is confirmed, additional laboratory and imaging tests typically are performed to determine aggressiveness or staging of the cancer.^1-3 Table 1 highlights the stages of prostate cancer.^1,3

Treatment Modalities and Available Therapeutics Treatment of prostate cancer is individualized; current options are based on factors including grade and stage of the cancer, as well as a patient’s health status and comorbidities, age, expected life span, and personal preferences.^1,4 Localized prostate cancer ranges from indolent disease not needing treatment or disease requiring some treatment to aggressive disease calling for multimodal treatment.^1,4 In older patients—such as men with medical conditions precluding surgery or radiation or those with an early-stage, slow-growing tumor providers may suggest “watchful waiting” to closely monitor disease progression rather than providing immediate treatment.^1,3

Surgery is the most common treatment option in cases where early-stage cancer is localized to the prostate and immediate surrounding tissue.^1,2 Prostatectomy involves removal of the entire prostate gland, attached seminal vesicles, and nearby tissue.¹ A second type of surgery, transurethral resection of the prostate, involves removal of prostate tissue by inserting a tube through the urethra.¹

For early-stage prostate cancer, radiation therapy is the second-most-common intervention and is limited to cases where the cancer is localized to the prostate gland.¹ Two types of radiation treatment designed to kill cancer cells are external beam radiation and brachytherapy, which uses implanted radioactive seeds.¹

Androgen deprivation therapy (ADT) is the most common treatment for more aggressive localized prostate cancer or for disease that has metastasized.^1,4 Because prostate cancer cells grow and feed on testosterone, ADT works by blocking its production or decreasing its effects in the body. However, in the treatment of prostate cancer, ADT is often accompanied by use of the following therapies³:

• Androgen blockade treatments including orchiectomy (surgical removal of the testicles, which produce testosterone) or use of medications to suppress hormone production
• Systemic hormone therapies, including luteinizing hormone–releasing hormone (LHRH) agonists, LHRH antagonists, antiandrogens, corticosteroids, estrogen, and androgen synthesis inhibitors
• Antiandrogen medications, which block receptors on prostate cancer cells from receiving testosterone
• Corticosteroids, such as prednisone, methylprednisolone, hydrocortisone, and dexamethasone, which can prevent the adrenal glands from producing testosterone
• Estrogens, which can stop the adrenal glands from producing testosterone, and androgen synthesis inhibitors, which can block androgen production

ADT is considered the first-line pharmacologic treatment for patients with advanced or metastatic prostate cancer, but many men with advanced disease eventually stop responding and are categorized as castration resistant.^3,4 Castration resistant prostate cancer (CRPC) is defined as a prostate cancer that progresses clinically, radiographically, or biochemically despite lowered levels of testosterone^.4

There are 4 different patient-specific groups in advanced disease: metastatic castration-resistant prostate cancer (mCRPC), metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castrationresistant prostate cancer (nmCRPC), and nonmetastatic castration-sensitive prostate cancer (nmCSPC).^1-3 For men who progress to CRPC, ADT with an LHRH agonist or antagonist is continued, but additional systemic therapies may be added depending on various patient and disease characteristics.^1,4

For aggressive cases, especially those where the cancer has spread outside the prostate, hormone therapy is often combined with chemotherapy, although chemotherapy may be used when hormone therapy is no longer effective.^1,4 Chemotherapy tends to be harsh on patients because it attacks and destroys the rapidly dividing cancer cells, but also kills normal cells. For men with bone metastases and CRPC, the addition of bone-modifying drugs such as denosumab (Xgeva; Amgen), zoledronic acid (Reclast; Novartis), or alendronate sodium (Binosto; ASCEND Therapeutics) is recommended.^3,4

PARP inhibitors are another class of medications with products that have become valuable treatment options.^5,6 PARP is a type of enzyme that helps repair DNA damage in cells.^5,6 As a type of targeted therapy, PARP inhibitors work by preventing cancer cells from repairing, thus allowing them to die.^5,6

Table 2 illustrates currently approved therapeutics in prostate cancer and their respective targets^.1

Evolving Landscape, Latest Key Takeaways in Prostate Cancer

The anticipated development of additional novel therapies in the near-term pipeline may continue to change standards of care in prostate cancer as well as expand the catalog of promising treatment options available to patients. Online Table 3 shows the current investigative entities in the near term pipeline for prostate cancer and their respective targets.

Because of its established efficacy across different patient specific groups, recent and planned expansions into additional patient populations, and a lack of near-term generic competition, enzalutamide (Xtandi; Astellas Pharma US, Inc and Pfizer Inc), a nextgeneration androgen receptor (AR) inhibitor, stands as a market leader in prostate cancer treatment.^1,5,6

Expansion opportunities in the future of enzalutamide for mCRPC patients include potential use in combination with PARP inhibitors.^5,6

In the current phase 3 EMBARK trial (NCT02319837) for nonmetastatic hormone-sensitive prostate cancer (nmHSPC), enzalutamide is being studied in combination with leuprolide.^1,5,6 This combination represents an opportunity to improve outcomes earlier in the treatment paradigm, but its uptake may be determined on justification of the clinical and financial considerations of enzalutamide treatment over existing localized options.

Since the 2018 US generic launch of abiraterone, use of blockbuster brand abiraterone acetate (Zytiga; Janssen Biotech, Inc) has declined, but the P450c17 inhibitor as part of standard regimens may expand to include several novel combinations^.5,6

Rucaparib (Rubraca; Clovis Oncology) and olaparib (Lynparza; AstraZeneca) are being studied in the firstline treatment of mCRPC: rucaparib plus enzalutamide vs enzalutamide alone and olaparib with abiraterone against abiraterone alone.^1,5,6 Most recently, the olaparib-abiraterone combination has shown top-line results with efficacy in patients regardless of homologous recombination repair status, opening a door for a label expansion opportunity.^1,5,6 Niraparib (Zejula; GSK) and talazoparib (Talzenna; Pfizer) are being researched in combination with next-generation treatments.^1,5,6 There is a relatively low prevalence of homologous recombination deficiency or BRCA biomarkers, which may limit the utility of PARP inhibitors with AR modulators, such as talazoparib with enzalutamide or niraparib with abiraterone in patients with mCRPC as first-line therapy options.^5,6

Expansion into earlier lines of therapy and additional patient populations is ongoing, but the treatment paradigm has shifted in patients with nmCRPC and nmHSPC because of next-generation AR inhibitors darolutamide (Nubeqa; Bayer) and apalutamide (Erleada; Janssen Biotech, Inc).^5,6 Bayer is seeking to expand the label for darolutamide for use in patients with high-risk localized disease and those with mHSPC. Apalutamide may be differentiated with an aggressive development plan to include potential expansion to patients with nmCRPC who are chemotherapy-naïve in combination with abiraterone and treating patients with localized disease previously treated with surgery or radiation.^1,5,6

Several checkpoint inhibitors are in development, but additional data from the ongoing trials will determine their future potential in prostate cancer. Pembrolizumab (Keytruda; Merck & Co, Inc) is being studied in combinations with olaparib, enzalutamide, and docetaxel for patients with mCRPC.^1,5,6 Nivolumab (Opdivo; Bristol Myers Squibb) is being evaluated with docetaxel. Atezolizumab (Tecentriq; Genentech USA, Inc), a PD-L1 antibody, is in phase 3 trials with enzalutamide or cabozantinib (Cabometyx; Exelixis, Inc) for patients with mCRPC after failure with nextgeneration hormone therapy.^1,5,6

In December 2020, oral GnRH receptor antagonist relugolix (Orgovyx; Myovant Sciences GmbH and Pfizer Inc) was approved. Data from the phase 3 HERO trial (NCT03085095) may enable its use in patients with localized definitive therapy also requiring ADT, as well as offer an intermittent ADT option in patients with advanced HSPC with a goal of minimizing potential adverse effects (AEs).^1,5,6

Gene therapy and cell therapy are overlapping fields of novel biomedical research with the goal of treating, preventing, or potentially curing diseases such as prostate cancer^.7 Gene
therapies function to correct genetic defects that may lead to growth of cancer cells, and may also treat diseases by replacing, inactivating, or introducing genes into the body, usually delivered through a viral vector.^7,8 The transferred genetic material can increase disease-fighting proteins or reduce the levels of disease-causing proteins.

Cell therapies target the delivery of immune cells with the goal of eradicating the cancer cells.^7,9 These therapies transfer modified live human cells into the body to restore or alter their functions and enhance their therapeutic potential.^7-9 The cells used can come from the patient (autologous cells) or a donor (allogeneic cells).^7-9

One example of cells originating from the patient is the chimeric antigen receptor (CAR) T-cell therapy.^7-9 This type of cell therapy removes the patient’s T cells and genetically reengineers them. These reengineered cells can then express a specific surface receptor that recognizes antigens of malignant cells, allowing T cells to bind and attack the tumor.^7-9

Bispecific T-cell engager therapy and CAR T therapies are being investigated as treatments for the prostate-specific membrane antigen (PSMA) or prostate stem cell antigen in patients with mCRPC, which typically overexpresses these ypes of antigens.^7-9 Radiolabeled lutein antibodies directed toward PSMA are also being investigated as options for imaging and treatment.

One potential breakthrough treatment in development for mCRPC is 177Lu-PSMA-617. This treatment has 2 components: a compound targeting the cancer cell protein PSMA and a precise radioactive particle that destroys cancer cells.¹ Healthy prostate cells do not contain PSMA, or do so at very low levels.^1,5,6

Conclusion
It is normal for patients to want to start treatment as soon as possible after diagnosis; however, prostate cancer can grow very slowly, so patients have options. The array of therapeutic selections for patients with prostate cancer has expanded in recent years and choices depend on patient preferences, signs and symptoms, biomarkers, presence or absence of visceral disease, and potential AEs.

Although selecting and sequencing optimal therapies for patients remains a challenge, newer study data arm patients and providers with information needed to make important treatment decisions. As practice standards evolve, specialty pharmacists can help develop individualized management plans for patients with prostate cancer involving the selection of optimal treatment strategies and approaches.

References

1. Biomedtracker. Informa Pharma Intelligence. Accessed March 4, 2022. biomedtracker.com

2. Key statistics for prostate cancer. American Cancer Society. Updated January 12, 2022. Accessed March 4, 2022. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html

3. NCCN Guidelines for Patients: prostate cancer early stage. National Comprehensive Cancer Network. 2022. Accessed March 4, 2022. www.nccn.org/patients/guidelines/content/PDF/prostate-early-patient.pdf

4. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: prostate cancer, version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143. doi:10.6004/jnccn.2021.0008

5. Oncology: Prostate Cancer. IPD Analytics. Accessed March 4, 2022. secure.ipdanalytics.com/User/Pharma/RxStrategy/Page/fb4b58a0-36f4-4e36-ae6e-2ab9e7c5ffc6#comment-groups6. Gray M. Disease analysis: prostate cancer. Datamonitor Healthcare. June 24, 2022. Accessed March 4, 2022. pharmastore.informa.com/product/disease analysis-prostate-cancer/

7. Different approaches. American Society of Gene + Cell Therapy. Updated November 5, 2021. Accessed March 4, 2022. patienteducation.asgct.org/gene-therapy-101/different-approaches

8. Mulholland EJ. Exploring gene and cell therapies for prostate cancer. American Society of Gene + Cell Therapy. November 19, 2020. Accessed March 4, 2022. asgct.org/research/news/november-2020/gene-and-cell-therapies-for-prostate-cancer

9. Gene and cell therapy FAQ’s. American Society of Gene + Cell Therapy. Accessed March 4, 2022. asgct.org/education/more-resources/gene-and-cell-therapy-faqs#:~:text=Gene%20therapy%20involves%20the%20transfer,relevant%20function%20into%20the%20patient

About the Author
Rachel K. Anderson, PharmD, CSP, is a clinical program manager at AllianceRx Walgreens Pharmacy.